Contrast in MRI is basically due to differences in relaxation times of water protons and it can be enhanced by the use of chemicals able to catalyse the relaxation processes of water protons. The most important class of MRI contrast agents is represented by the Gd(III) chelates which are currently used in about ⅓ of the clinical tests. To be considered as a potentially valuable MRI contrast agent, a Gd(III) complex must display a high thermodynamic (and possibly kinetic) stability in order to ensure against the release of free Gd(III) ions and ligands, both known to be toxic for living organisms. Therefore, known chelating compounds, including octa-coordinating ligands such as, for instance, diethylenetriaminopentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (ROTA) and their derivatives, have been considered for the chelation of the Gd(III) ion. These ligands wrap around this lanthanide(III) ion and leave one binding site available for the coordination of one water molecule. Thus, the coordinated water protons display a very short relaxation time (T1M) that is transferred to the “bulk” water molecules by the occurrence of a fast exchange process (Kex=1/τM). See, for a general reference, Aime S.; Botta M.; Fasano, M.; Terreno, E. Chem. Soc. Rev. 1998, 27, 19-29.
As far as the relaxation enhancement property is concerned, a paramagnetic Gd(III) complex is characterized by its relaxivity (r1p) which represents the increase of the proton relaxation rate of an aqueous solution of the Gd(III) complex in comparison to the proton relaxation rate of neat water (R1°). The relaxivity is usually measured at 298K and 20 MHz (0.5 T).
On the other side, when a different property such as the pharmacokinetic profile is considered for a Gd-complex or, more generally, for a paramagnetic chelate complex or a paramagnetic contrast agent, the following categories of diagnostics may be identified:
Non-Specific Agents (NSA) that freely and quickly distribute into the extracellular space after administration; Low Diffusion Agents (LDA) that may only diffuse slowly from the blood system into the extracellular space; and Blood Pool Agents that mainly distribute, if not completely, into the blood system.
Because of their biodistribution profile, the NSA are thus designed for general use. As an example, the NSA agents below which are currently used in clinical practice display almost identical relaxivity of approximately 4.7 mM−1 s−1 (measured at 298K and 20 MHz).

Since higher relaxivity leads to better contrast differentiation in MR images, much attention has been devoted in the last two decades to the search for systems with higher relaxivities than those found in commercial products.
In this respect, it was recognised that for Gd(III) complexes, which coordinated water molecules were in fast exchange with the “bulk” water, the r1p values increased linearly with the increase of their Molecular Weight (MW). This behaviour is fully consistent with the known dependence of T1M from the molecular reorientational time (τR) (see the aforementioned reference).
On this basis, two pathways have been followed to lengthen the molecular reorientational time: i) the covalent route, consisting of binding bulky moieties on the surface of the ligand; and the non-covalent route, consisting of systems able to form supramolecular adducts with slowly moving substrates. For this latter approach, the most commonly used substrate is represented by Human Serum Albumin (HSA) and several Gd(III) chelates containing suitable substituents for a high affinity binding to the serum protein have been reported. Upon binding to HSA, these Gd(III) complexes display their maximum r1p value at observation frequencies of 25-30 MHz, i.e. at magnetic field strength close to 1 T. At higher fields, however, their r1p decreases quickly thus showing that the strong effect of τR on T1M is mostly important at imaging fields ranging between 0.5 and 1.5 T. See, for a general reference: Aime S., Botta M., Fasano, M.; Terreno, E. Chem. Soc. Rev. 1998, 27, 19-29; and Caravan P., Cloutier N. J., Matthew T., Lauffer R. B. et al. JACS, 2002, 124, 3152-3162.
For clinical applications the current trend is to move to tomographs operating at 3 T so as to obtain a better imaging resolution. Therefore, there is the need to identify new ways to attain high relaxivities over an extended range of magnetic field strength.
Moreover, in view of their increased size, these high MW Contrast agents have an almost unique localization in the body vascular system and this biodistribution pattern, characterizing them as “blood-pool” contrast agents, limit their use accordingly.
When considering MRI contrast agents with high relaxivity, some further compounds exist having MW lower than those of the blood pool agents but still exhibiting a relaxivity up to 25 mM−1·s−1 measured at 20 MHz and 37° C. (see, for instance, WO 00/75141; and J. Magn. Reson. Imaging 2000, 11:182-191).
These compounds are known as Low Diffusion Agents (LDA) because their MW, ranging from 5 to 10 kDa, is high enough to allow only their low diffusion into the extravascular space. Because of their pharmacokinetic profile, the diagnostic applications of these LDA are different from those of the already marketed NSA which, by freely diffusing from the vascular bed, are consequently designed for a general diagnostic application.
There is therefore the need for new and improved NSA able to combine free and rapid biodistribution, and consequent general usefulness, with high relaxivity.
The present invention thus relates to a novel class of contrast agents, essentially characterized by the presence of hydroxylated groups, that satisfy the above requirements.